Neonatal bacterial infection is a major cause of morbidity in the United States today. Bacterial infections are even more dangerous for neonates who are Very Low Birth Weight (VLBW) since the immune system of these neonates is severely compromised. The overall immune system of neonates has several components each of which work to complement one another. The two major components of the overall immune system in neonates are the neutrophil-macrophage phagocytic system and the antibody-mediated immunity system. In a healthy neonate these systems are able to protect the neonate against bacterial and viral infections. However, in a neonate in which these systems are compromised the likelihood of bacterial or viral infection is extremely high and usually results in death.
The neutrophil-macrophage phagocytic system utilizes neutrophils, the chief phagocytotic leukocyte of the blood, to phagocytose and destroy small organisms, especially bacteria, which are present in the host. However, in neonates that have substantial deficiencies in the phagocytic system the ability for this system to effectively protect against bacterial invasion is severely impaired.
A second system of the immune system is the antibody-mediated immune system. This system utilizes immunoglobulins, such as antibodies, to circulate in the bloodstream and other body fluids, where they bind specifically to the foreign antigen that induced them. Binding of the antibody inactivates viruses and bacterial toxins by blocking their ability to bind receptors on target cells. Antibody binding also marks invading microorganisms for destruction, either by making it easier for a phagocytic cell (such as neutrophils) to ingest them or by activating a system of blood particles that kills the invader. The antibody-mediated immune system of healthy neonates is generally very immature and therefore is not truly effective in protecting neonates against bacterial infection at this early stage of life. In addition, the antibody-mediated immune system is only as effective as the neutrophil macrophage-phagocytic system since the antibody-mediated immune system depends on neutrophils to ingest and destroy all foreign particles tagged by the serum antibodies. Since the absolute neutrophil count (ANC) in neonates is naturally low, the antibody-mediated immunity system is also impaired. Those neonates in which their antibody-meditated immune system is even further compromised have virtually no antibody-mediated immune system at all and therefore depend solely on the neutrophil-macrophage phagocytic system to protect them against bacterial, fungal and viral infections.
Under normal conditions the production of neutrophils is increased under the influence of G-CSF. G-CSF is one of the hematopoietic growth factors that stimulates committed progenitor cells to proliferate and to form colonies of differentiating blood cells, preferentially neutrophils.
G-CSF has been found to be useful in the treatment of patients where the increase in neutrophils will provide additional protection from viral, fungal and bacterial infection. For example, U.S. Pat. No. 5,536,495 describes the use of G-CSF to reduce the occurrence of acute rejection as well as to reduce infections that are associated with organ transplants. Administering G-CSF to transplant patients has been successful in increasing the production of neutrophils in the blood, which in turn increased the patient's ability to ward-off infection.
Similarly, there is a need for a method of use for the administration of G-CSF to neutropenic neonates so as to enhance their immune systems by stimulating the production of neutrophils in the blood and/or causing the modulation of expression of effector cell molecules on the surface of the neutrophils.
Certain receptors which are present on the surface of neutrophils facilitate elimination of antibody-coated neonatal pathogens including bacteria and fungi through opsonization, enhanced chemotaxis and increased cytotoxic killing. Low levels of these receptors are thought to contribute to an increased susceptibility of sick VLBW neonates to infections with these organisms.
A method of using G-CSF to stimulate the production of neutrophils and/or modulate the production of the expression of effector cell molecules on neutrophils in neonates is desirable.